Simian virus 40 (SV40 is a DNA virus which specifically induces mesotheliomas, ependymomas, sarcomas and osteosarcomas in rodents. These same tumor types contain SV40 sequences in humans, but the role of SV40 in human carcinogenesis is unknown. We are investigating if SV40 contributes to the development of human mesothelioma, a very aggressive tumor of the pleura whose incidence continues to increase. Mesothelioma is strongly associated with asbestos exposure, but only 5-10 percent of workers exposed to high levels of asbestos develop this tumor, and about 20 percent of mesotheliomas patients have not been exposed to asbestos. It would be very important to find the co-factor/s that render some workers more susceptible to asbestos or that cause mesothelioma in individuals who have not been exposed to asbestos. We propose to investigate the mechanisms that make mesothelial cells very susceptible to SV40-mediated transformation, and their possible relevance to human malignant mesothelioma. During the previous grant period, we established the possible biological significance of SV40 when present in some human mesotheliomas, and the utility of an in vitro SV40-human mesothelial cell system for studying this association. We propose to build on these studies to identify: 1) the natural history of SV40 infection in humans, 2) the mechanisms that cause the frequent immortalization of mesothelial cells following infection with SV40, 3) the mechanisms which may account for the presence of the more rapidly replicating non-archetypal SV40 in mesotheliomas, compared to the less rapidly replicating archetypal SV40 in ependymomas and bone tumors, and whether these mechanisms are related to oncogenesis.